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  • Review Article
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Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer

Nature Reviews Gastroenterology & Hepatology volume 6, pages 297–305 (2009)Cite this article

Abstract

In patients with IBD, chronic colonic inflammation increases the risk of colorectal cancer, perhaps because inflammation predisposes these tissues to genomic instability. Carcinogenesis in the inflamed colon seems to follow a different sequence of genetic alterations than that observed in sporadic cancers in the uninflamed colon. In this Review, we focus on the genetic alterations in colitis-associated colorectal cancer that contribute to the acquisition of the essential hallmarks of cancer, and on how those alterations differ from sporadic colorectal cancers. Our intent is to provide a conceptual basis for categorizing carcinogenetic molecular abnormalities in IBD, and for understanding how cancer-preventive therapies might target reversal of acquired abnormalities in specific biochemical pathways.

Key Points

  • Chronic colonic inflammation, as occurs in IBD, increases the risk of colorectal cancer, perhaps because inflammation predisposes to genomic instability

  • Carcinogenesis in IBD seems to follow a different sequence of genetic alterations to that observed in sporadic colorectal cancers

  • The molecular alterations that occur in colitis-related carcinogenesis can generally be categorized as endowing cells in the gastrointestinal tract, with one of six hallmarks of cancer cells

  • The essential hallmarks of cancer cells are: proliferation self-sufficiency; resistance to growth-inhibitory signals; avoidance of apoptosis; resisting senescence; belonging to tissues with sustained angiogenesis; and tissue invasion and metastasis

  • An important, emerging concept in colorectal carcinogenesis is that cancers arise from tissue-specific stem cells

  • Understanding the molecular mechanisms of carcinogenesis in IBD-related colorectal cancers will aid in the prevention and treatment of these cancers

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Figure 1: Genetic markers, including upregulation (↑) or downregulation (↓) of gene or protein expression, potentially associated with onset of colitis-associated colorectal carcinoma or of those clinical conditions (chronic inflammation and dysplasia) that progressively lead to the onset of colitis-associated colorectal carcinoma.
Figure 2: Proposed role of inflammation in colitis-associated CRC.

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References

  1. Eaden, J. A., Abrams, K. R. & Mayberry, J. F. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 48, 526–535 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Ekbom, A., Helmickm, C., Zack, M. & Adami, H. O. Ulcerative colitis and colorectal cancer. A population-based study. N. Engl. J. Med. 323, 1228–1233 (1990).

    CAS  PubMed  Google Scholar 

  3. Weedon, D. D., Shorter, R. G., Ilstrup, D. M., Huizenga, K. A. & Taylor, W. F. Crohn's disease and cancer. N. Engl. J. Med. 289, 1099–1103 (1973).

    CAS  PubMed  Google Scholar 

  4. Gyde, S. N. et al. Malignancy in Crohn's disease. Gut 21, 1024–1029 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bernstein, C. N., Blanchard, J. F., Kliewer, E. & Wajda, A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 91, 854–862 (2001).

    CAS  PubMed  Google Scholar 

  6. Canavan, C., Abrams, K. R. & Mayberry, J. Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn's disease. Aliment. Pharmacol. Ther. 23, 1097–1104 (2006).

    CAS  PubMed  Google Scholar 

  7. Freeman, H. J. Colorectal cancer risk in Crohn's disease. World J. Gastroenterol. 14, 1810–1811 (2008).

    PubMed  PubMed Central  Google Scholar 

  8. Rutter, M. et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126, 451–459 (2004).

    PubMed  Google Scholar 

  9. Gupta, R. B. et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology 133, 1099–1105 (2007).

    PubMed  Google Scholar 

  10. Macdougall, I. P. The cancer risk in ulcerative colitis. Lancet 2, 655–658 (1964).

    CAS  PubMed  Google Scholar 

  11. Farmer, R. G. & Brown, C. H. Ulcerative proctitis: course and prognosis. Gastroenterology 51, 219–223 (1966).

    CAS  PubMed  Google Scholar 

  12. Kvist, N. et al. Malignancy in ulcerative colitis. Scand. J. Gastroenterol. 24, 497–506 (1989).

    CAS  PubMed  Google Scholar 

  13. Brentnall, T. A. et al. Risk and natural history of colonic neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis. Gastroenterology 110, 331–338 (1996).

    CAS  PubMed  Google Scholar 

  14. Askling, J. et al. Family history as a risk factor for colorectal cancer in inflammatory bowel disease. Gastroenterology 120, 1356–1362 (2001).

    CAS  PubMed  Google Scholar 

  15. Nuako, K. W. et al. Familial predisposition for colorectal cancer in chronic ulcerative colitis: a case-control study. Gastroenterology 115, 1079–1083 (1998).

    CAS  PubMed  Google Scholar 

  16. Kornbluth, A. & Sachar, D. B. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. Am. J. Gastroenterol. 99, 1371–1385 (2004).

    PubMed  Google Scholar 

  17. Fenoglio-Preiser, C. M. Gastrointestinal Pathology: An Atlas and Text (Lippincott Williams & Wilkins, Philadelphia, 1999).

    Google Scholar 

  18. Rubin, D. T. & Turner, J. R. Surveillance of dysplasia in inflammatory bowel disease: the gastroenterologist–pathologist partnership. Clin. Gastroenterol. Hepatol. 4, 1309–1313 (2006).

    PubMed  PubMed Central  Google Scholar 

  19. Rutter, M. D. et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 130, 1030–1038 (2006).

    PubMed  Google Scholar 

  20. Ullman, T., Croog, V., Harpaz, N., Sachar, D. & Itzkowitz, S. Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 125, 1311–1319 (2003).

    PubMed  Google Scholar 

  21. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  PubMed  Google Scholar 

  22. Zhang, H. Y., Spechler, S. J. & Souza, R. F. Esophageal adenocarcinoma arising in Barrett esophagus. Cancer Lett. 275, 170–177 (2008).

    PubMed  PubMed Central  Google Scholar 

  23. McKay, C. J., Glen, P. & McMillan, D. C. Chronic inflammation and pancreatic cancer. Best Pract. Res. Clin. Gastroenterol. 22, 65–73 (2008).

    CAS  PubMed  Google Scholar 

  24. Genta, R. M. The gastritis connection: prevention and early detection of gastric neoplasms. J. Clin. Gastroenterol. 36 (Suppl. 5), 44–49 (2003).

    Google Scholar 

  25. Kawanishi, S., Hiraku, Y., Pinlaor, S. & Ma, N. Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. Biol. Chem. 387, 365–372 (2006).

    CAS  PubMed  Google Scholar 

  26. Meira, L. B. et al. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J. Clin. Invest. 118, 2516–2525 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Liao, J. et al. Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice. Mol. Carcinog. 47, 638–646 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Garrity-Park, M. M., Loftus, E. V. Jr, Bryant, S. C., Sandborn, W. J. & Smyrk, T. C. Tumor necrosis factor-alpha polymorphisms in ulcerative colitis-associated colorectal cancer. Am. J. Gastroenterol. 103, 407–415 (2008).

    CAS  PubMed  Google Scholar 

  29. Suchy, J. et al. Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk. BMC Cancer 8, 112 (2008).

    PubMed  PubMed Central  Google Scholar 

  30. Crivello, A. et al. Regulatory cytokine gene polymorphisms and risk of colorectal carcinoma. Ann. NY Acad. Sci. 1089, 98–103 (2006).

    CAS  PubMed  Google Scholar 

  31. Norris, S. et al. Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: the role of MICA polymorphism. Gastroenterology 120, 1475–1482 (2001).

    CAS  PubMed  Google Scholar 

  32. Maggs, J. R. & Chapman, R. W. An update on primary sclerosing cholangitis. Curr. Opin. Gastroenterol. 24, 377–383 (2008).

    PubMed  Google Scholar 

  33. Elias, E. & Mills, C. O. Co-ordinated defence and the liver. Clin. Med. 7, 180–184 (2007).

    Google Scholar 

  34. Siviero, I., Ferrante, S. M., Meio, I. B., Madi, K. & Chagas, V. L. Hepatobiliary effects of cholic and lithocholic acids: experimental study in hamsters. Pediatr. Surg. Int. 24, 325–331 (2008).

    PubMed  Google Scholar 

  35. Hofmann, A. F. Detoxification of lithocholic acid, a toxic bile acid: relevance to drug hepatotoxicity. Drug Metab. Rev. 36, 703–722 (2004).

    CAS  PubMed  Google Scholar 

  36. van Dieren, J. M. et al. Chromosomal and microsatellite instability of adenocarcinomas and dysplastic lesions (DALM) in ulcerative colitis. Diagn. Mol. Pathol. 15, 216–222 (2006).

    CAS  PubMed  Google Scholar 

  37. Willenbucher, R. F. et al. Genomic instability is an early event during the progression pathway of ulcerative-colitis-related neoplasia. Am. J. Pathol. 154, 1825–1830 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Rabinovitch, P. S. et al. Pancolonic chromosomal instability precedes dysplasia and cancer in ulcerative colitis. Cancer Res. 59, 5148–5153 (1999).

    CAS  PubMed  Google Scholar 

  39. Rubin, C. E. et al. DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. Gastroenterology 103, 1611–1620 (1992).

    CAS  PubMed  Google Scholar 

  40. Lindberg, J. O., Stenling, R. B. & Rutegård, J. N. DNA aneuploidy as a marker of premalignancy in surveillance of patients with ulcerative colitis. Br. J. Surg. 86, 947–950 (1999).

    CAS  PubMed  Google Scholar 

  41. Befrits, R., Hammarberg, C., Rubio, C., Jaramillo, E. & Tribukait, B. DNA aneuploidy and histologic dysplasia in long-standing ulcerative colitis. A 10-year follow-up study. Dis. Colon Rectum 37, 313–319 (1994).

    CAS  PubMed  Google Scholar 

  42. Löfberg, R., Broström, O., Karlén, P., Ost, A. & Tribukait, B. DNA aneuploidy in ulcerative colitis: reproducibility, topographic distribution, and relation to dysplasia. Gastroenterology 102, 1149–1154 (1992).

    PubMed  Google Scholar 

  43. Löfberg, R., Tribukait, B., Ost. A., Broström, O. & Reichard, H. Flow cytometric DNA analysis in longstanding ulcerative colitis: a method of prediction of dysplasia and carcinoma development? Gut 28, 1100–1106 (1987).

    PubMed  PubMed Central  Google Scholar 

  44. Yamada, S., Yashiro, M., Maeda, K., Nishiguchi, Y. & Hirakawa, K. A novel high-specificity approach for colorectal neoplasia: detection of K-ras2 oncogene mutation in normal mucosa. Int. J. Cancer 113, 1015–1021 (2005).

    CAS  PubMed  Google Scholar 

  45. Chen, J., Compton, C., Cheng, E., Fromowitz, F. & Viola, M. V. c-Ki-ras mutations in dysplastic fields and cancers in ulcerative colitis. Gastroenterology 102, 1983–1987 (1992).

    CAS  PubMed  Google Scholar 

  46. Umetani, N. et al. Genetic alterations in ulcerative colitis-associated neoplasia focusing on APC., K-ras gene and microsatellite instability. Jpn J. Cancer Res. 90, 1081–1087 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Tyner, A. L. & Omary, M. B. Signal transduction pathways during oncogenesis. In Gastrointestinal Cancers ed. Rustgi, A. K. 61 (Saunders, Edinburgh, 2003).

    Google Scholar 

  48. Cartwright, C. A., Coad, C. A. & Egbert, B. M. Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis. J. Clin. Invest. 93, 509–515 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ewen, M. E. The mammalian cell cycle. In Gastrointestinal Cancers ed. Rustgi, A. K. 3–12 (Saunders, Edinburgh, 2003).

    Google Scholar 

  50. Wong, N. A. et al. Cyclin D1 and p21 in ulcerative colitis-related inflammation and epithelial neoplasia: a study of aberrant expression and underlying mechanisms. Hum. Pathol. 34, 580–588 (2003).

    CAS  PubMed  Google Scholar 

  51. Maeda, K. et al. Overexpression of cyclin D1 and p53 associated with disease recurrence in colorectal adenocarcinoma. Int. J. Cancer 74, 310–315 (1997).

    CAS  PubMed  Google Scholar 

  52. Beck, P. L. & Podolsky, D. K. Growth factors in inflammatory bowel disease. Inflamm. Bowel Dis. 5, 44–60 (1999).

    CAS  PubMed  Google Scholar 

  53. Sinha, A., Nightingale, J., West, K. P., Berlanga-Acosta, J. & Playford, R. J. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N. Engl. J. Med. 349, 350–357 (2003).

    CAS  PubMed  Google Scholar 

  54. Makiyama, K., Takeshima, F. & Hamamoto, T. Efficacy of rebamipide enemas in active distal ulcerative colitis and proctitis: a prospective study report. Dig. Dis. Sci. 50, 2323–2329 (2005).

    CAS  PubMed  Google Scholar 

  55. Ponz-Sarvise, M. et al. Epidermal growth factor receptor inhibitors in colorectal cancer treatment: what's new? World J. Gastroenterol. 13, 5877–5887 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Alexander, R. J., Panja, A., Kaplan-Liss, E., Mayer, L. & Raicht, R. F. Expression of growth factor receptor-encoded mRNA by colonic epithelial cells is altered in inflammatory bowel disease. Dig. Dis. Sci. 40, 485–494 (1995).

    CAS  PubMed  Google Scholar 

  57. Alberts, B. et al. Finding the cancer-critical genes. In Molecular Biology of the Cell eds Alberts, B. et al. 1333–1340 (Garland Science, New York, 2002).

    Google Scholar 

  58. Lewin, B. Oncogenes and cancer. In Genes VII, 875–912 (Oxford Press, New York, 2002).

    Google Scholar 

  59. Itzkowitz, S. H. Molecular biology of dysplasia and cancer in inflammatory bowel disease. Gastroenterol. Clin. N. Am. 35, 553–571 (2006).

    Google Scholar 

  60. Powell, S. M. et al. APC mutations occur early during colorectal tumorigenesis. Nature 359, 235–237 (1992).

    CAS  PubMed  Google Scholar 

  61. Carethers, J. M. Biology and genetics of colorectal cancer. In Gastrointestinal Cancers ed. Rustgi, A. K. 407–417 (Saunders, Edinburgh, 2003).

    Google Scholar 

  62. Brentnall, T. A. et al. Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenterology 107, 369–378 (1994).

    CAS  PubMed  Google Scholar 

  63. Burmer, G. C. et al. Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele. Gastroenterology 103, 1602–1610 (1992).

    CAS  PubMed  Google Scholar 

  64. Harpaz, N. et al. p53 protein expression in ulcerative colitis-associated colorectal dysplasia and carcinoma. Hum. Pathol. 25, 1069–1074 (1994).

    CAS  PubMed  Google Scholar 

  65. Holzmann, K. et al. Comparative analysis of histology, DNA content, p53 and Ki-ras mutations in colectomy specimens with long-standing ulcerative colitis. Int. J. Cancer 76, 1–6 (1998).

    CAS  PubMed  Google Scholar 

  66. Hussain, S. P. et al. Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res. 60, 3333–3337 (2000).

    CAS  PubMed  Google Scholar 

  67. Aust, D. E. et al. Chromosomal alterations in ulcerative colitis-related and sporadic colorectal cancers by comparative genomic hybridization. Hum. Pathol. 31, 109–114 (2000).

    CAS  PubMed  Google Scholar 

  68. Willenbucher, R. F., Zelman, S. J., Ferrell, L. D., Moore, D. H. Jr & Waldman, F. M. Chromosomal alterations in ulcerative colitis-related neoplastic progression. Gastroenterology 113, 791–801 (1997).

    CAS  PubMed  Google Scholar 

  69. Hsieh, C. J. et al. Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res. 58, 3942–3945 (1998).

    CAS  PubMed  Google Scholar 

  70. Sato, F. et al. Hypermethylation of the p14(ARF) gene in ulcerative colitis-associated colorectal carcinogenesis. Cancer Res. 62, 1148–1151 (2002).

    CAS  PubMed  Google Scholar 

  71. Moriyama, T. et al. Hypermethylation of p14 (ARF) may be predictive of colitic cancer in patients with ulcerative colitis. Dis. Colon Rectum 50, 1384–1392 (2007).

    PubMed  Google Scholar 

  72. Barnard, J. A. Peptide growth factors. In Gastrointestinal Cancers ed. Rustgi, A. K. 36 (Saunders, Edinburgh, 2003).

    Google Scholar 

  73. Souza, R. F. et al. A transforming growth factor β1 receptor type II mutation in ulcerative colitis-associated neoplasms. Gastroenterology 112, 40–45 (1997).

    CAS  PubMed  Google Scholar 

  74. Liu, X. H., Yao, S., Kirschenbaum, A. & Levine, A. C. NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and downregulates bcl-2 expression in LNCaP cells. Cancer Res. 58, 4245–4249 (1998).

    CAS  PubMed  Google Scholar 

  75. Elder, D. J., Halton, D. E., Hague, A. & Paraskeva, C. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: independence from COX-2 protein expression. Clin. Cancer Res. 3, 1679–1683 (1997).

    CAS  PubMed  Google Scholar 

  76. Fukata, M. et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133, 1869–1881 (2007).

    CAS  PubMed  Google Scholar 

  77. Agoff, S. N. et al. The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia. Am. J. Pathol. 157, 737–745 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Eberhart, C. E. et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107, 1183–1188 (1994).

    CAS  PubMed  Google Scholar 

  79. Oshima, M. et al. Suppression of intestinal polyposis in Apc δ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87, 803–809 (1996).

    CAS  PubMed  Google Scholar 

  80. Kohno, H., Suzuki, R., Sugie, S. & Tanaka, T. Suppression of colitis-related mouse colon carcinogenesis by a COX-2 inhibitor and PPAR ligands. BMC Cancer 5, 46 (2005).

    PubMed  PubMed Central  Google Scholar 

  81. Inoue, T. et al. Therapeutic effect of nimesulide on colorectal carcinogenesis in experimental murine ulcerative colitis. J. Gastroenterol. Hepatol. 22, 1474–1481 (2007).

    CAS  PubMed  Google Scholar 

  82. Mukawa, K. et al. Inhibitory effects of the cyclooxygenase-2 inhibitor, etodolac, on colitis-associated tumorigenesis in p53-deficient mice treated with dextran sulfate sodium. Oncol. Rep. 19, 393–399 (2008).

    CAS  PubMed  Google Scholar 

  83. Bresalier, R. S. et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N. Engl. J. Med. 352, 1092–1102 (2005).

    CAS  PubMed  Google Scholar 

  84. Osborn, N. K. et al. Aberrant methylation of the eyes absent 4 gene in ulcerative colitis-associated dysplasia. Clin. Gastroenterol. Hepatol. 4, 212–218 (2006).

    CAS  PubMed  Google Scholar 

  85. Holzmann, K. et al. Telomerase activity in long-standing ulcerative colitis. Anticancer Res. 20, 3951–3955 (2000).

    CAS  PubMed  Google Scholar 

  86. Sipos, F. et al. Elevated insulin-like growth factor 1 receptor, hepatocyte growth factor receptor and telomerase protein expression in mild ulcerative colitis. Scand. J. Gastroenterol. 43, 289–298 (2008).

    CAS  PubMed  Google Scholar 

  87. Griga, T., May, B., Pfisterer, O., Müller, K. M. & Brasch, F. Immunohistochemical localization of vascular endothelial growth factor in colonic mucosa of patients with inflammatory bowel disease. Hepatogastroenterology 49, 116–123 (2002).

    PubMed  Google Scholar 

  88. Tsiolakidou, G., Koutroubakis, I. E., Tzardi, M. & Kouroumalis, E. A. Increased expression of VEGF and CD146 in patients with inflammatory bowel disease. Dig. Liver Dis. 40, 673–679 (2008).

    CAS  PubMed  Google Scholar 

  89. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).

    CAS  PubMed  Google Scholar 

  90. Klein, B. & Gottfried, M. Targeted agents to improve treatment results in colon cancer: bevacizumab and cetuximab. J. BUON 12 (Suppl. 1), 127–136 (2007).

    Google Scholar 

  91. Dorudi, S., Sheffield, J. P., Poulsom, R., Northover, J. M. & Hart, I. R. E-cadherin expression in colorectal cancer. An immunocytochemical and in situ hybridization study. Am. J. Pathol. 142, 981–986 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Hill, K. A. et al. Comparative analysis of cell adhesion molecules, cell cycle regulatory proteins, mismatch repair genes, cyclooxygenase-2, and DPC4 in carcinomas arising in inflammatory bowel disease and sporadic colon cancer. Oncol. Rep. 11, 951–956 (2004).

    CAS  PubMed  Google Scholar 

  93. van Dekken, H. et al. Wnt pathway-related gene expression during malignant progression in ulcerative colitis. Acta Histochem. 109, 266–272 (2007).

    CAS  PubMed  Google Scholar 

  94. Itoh, F., Yamamoto, H., Hinoda, Y. & Imai, K. Enhanced secretion and activation of matrilysin during malignant conversion of human colorectal epithelium and its relationship with invasive potential of colon cancer cells. Cancer 77 (Suppl. 8), 1717–1721 (1996).

    CAS  PubMed  Google Scholar 

  95. Newell, K. J., Matrisian, L. M. & Driman, D. K. Matrilysin (matrix metalloproteinase-7) expression in ulcerative colitis-related tumorigenesis. Mol. Carcinog. 34, 59–63 (2002).

    CAS  PubMed  Google Scholar 

  96. Bresalier, R. S. et al. Liver metastasis and adhesion to the sinusoidal endothelium by human colon cancer cells is related to mucin carbohydrate chain length. Int. J. Cancer 76, 556–562 (1998).

    CAS  PubMed  Google Scholar 

  97. Itzkowitz, S. H. et al. Sialosyl-Tn antigen: initial report of a new marker of malignant progression in long-standing ulcerative colitis. Gastroenterology 109, 490–497 (1995).

    CAS  PubMed  Google Scholar 

  98. Bresalier, R. S. et al. Enhanced sialylation of mucin-associated carbohydrate structures in human colon cancer metastasis. Gastroenterology 11, 1354–1167 (1996).

    Google Scholar 

  99. Al-Hajj, M. & Clarke, M. F. Self-renewal and solid tumor stem cells. Oncogene 23, 7274–7282 (2004).

    CAS  PubMed  Google Scholar 

  100. Collins, A. T., Berry, P. A., Hyde, C., Stower, M. J. & Maitland, N. J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65, 10946–10951 (2005).

    CAS  PubMed  Google Scholar 

  101. Fang, D. et al. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res. 65, 9328–9337 (2005).

    CAS  PubMed  Google Scholar 

  102. Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030–1037 (2007).

    CAS  PubMed  Google Scholar 

  103. Ma, S. et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132, 2542–2556 (2007).

    CAS  PubMed  Google Scholar 

  104. Prince, M. E. et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc. Natl Acad. Sci. USA 104, 973–978 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Ricci-Vitiani, L. et al. Identification and expansion of human colon cancer-initiating cells. Nature 445, 111–115 (2007).

    CAS  PubMed  Google Scholar 

  106. O'Brien, C. A., Pollett, A., Gallinger, S. & Dick, J. E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007).

    CAS  PubMed  Google Scholar 

  107. Horst, D., Krieg, L., Engel, J., Kirchner, T. & Jung, A. CD133 expression is an independent prognostic marker for low survival in colorectal cancer. Br. J. Cancer 99, 1285–1289 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Ricci-Vitiani, L., Pagliuca, A., Palio, E., Zeuner, A. & De Maria, R. Colon cancer stem cells. Gut 57, 538–548 (2008).

    CAS  PubMed  Google Scholar 

  109. Dalerba, P. et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl Acad. Sci. USA 104, 10158–10163 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. May, R. et al. Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice. Stem Cells 26, 630–637 (2008).

    PubMed  Google Scholar 

  111. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    CAS  PubMed  Google Scholar 

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  1. Dallas Veterans Affairs Medical Center, and University of Texas Southwestern Medical Center, Dallas, TX, USA

    Linda A. Feagins, Rhonda F. Souza & Stuart J. Spechler

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L. A. Feagins declared association with the following company: Centocor, as recipient of grant/research support. RF Souza declared associations with the following companies: AstraZeneca, as consultant and recipient of grant/research support, and TAP Pharmaceutical Products, as consultant. SJ Spechler declared associations with the following companies: AstraZeneca, as consultant and recipient of grant/research support, Takeda, as recipient of grant/research support, and Bârrx Medical as recipient of grant/research support.

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Feagins, L., Souza, R. & Spechler, S. Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer. Nat Rev Gastroenterol Hepatol 6, 297–305 (2009). https://doi.org/10.1038/nrgastro.2009.44

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